Bunting EL, Donaldson J, Cumming SA, Olive J, Broom E, Miclăuș M, Hamilton J, Tegtmeyer M, Zhao HT, Brenton J, Lee WS, Handsaker RE, Li S, Ford B, Ryten M, McCarroll SA, Kordasiewicz HB, Monckton DG, Balmus G, Flower M, Tabrizi SJ. Antisense oligonucleotide-mediated MSH3 suppression reduces somatic CAG repeat expansion in Huntington's disease iPSC-derived striatal neurons. Sci Transl Med. 2025 Feb 12;17(785):eadn4600. Epub 2025 Feb 12 PubMed.
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Penn Medicine
Over the last couple of decades, researchers have found that a tandem repeat that causes Huntington’s disease becomes unstable in certain vulnerable cell populations in patients’ brains, and that this instability drives disease progression. Moreover, we have found that genetic variation elsewhere in the genome modifies the tandem repeat instability, including at the MSH3 gene. Leveraging these genetic findings, the authors targeted MSH3 using antisense oligonucleotide therapy. They find that reduction of MSH3 levels ameliorates tandem repeat instability in both a cell-line model and a mouse model.
The application of antisense oligonucleotide therapies is advantageous because this modality has already been used for established therapies for other neurological diseases. The authors’ work represents an important first step in showing that reducing MSH3 can reduce tandem repeat instability without causing obvious adverse effects on cell health. Future work will be needed to figure out if this therapy ultimately slows down progression of Huntington’s.
This work represents an exciting translation of human genetic modifier findings to potential therapies for this devastating disease. It also has important implications beyond Huntington’s. There are approximately 60 other rare disorders, including forms of frontotemporal dementia, that are caused by a specific expansion in a tandem repeat. Many of these other disorders have also been demonstrated to display instability of the pathogenic tandem repeat in specific tissues. Thus, modifying levels of MSH3 and other DNA repair proteins represents a potential therapeutic strategy with applicability to many rare disorders beyond Huntington’s disease.
Moreover, our team and others have recently identified that tandem repeats are expanded in Alzheimer’s disease. If instability of these tandem repeats also occurs in the brains of patients with Alzheimer’s, then therapeutic modification of MSH3 may have treatment implications for this very common condition.
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